2-241735267-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152783.5(D2HGDH):c.43C>G(p.Arg15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,518,798 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R15R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0084 (51 hom., cov: 34)
  • Exomes 𝑓: 0.0058 (352 hom.)
• Consequence: D2HGDH NM_152783.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.861

Genes affected

D2HGDH (HGNC:28358): (D-2-hydroxyglutarate dehydrogenase) This gene encodes D-2hydroxyglutarate dehydrogenase, a mitochondrial enzyme belonging to the FAD-binding oxidoreductase/transferase type 4 family. This enzyme, which is most active in liver and kidney but also active in heart and brain, converts D-2-hydroxyglutarate to 2-ketoglutarate. Mutations in this gene are present in D-2-hydroxyglutaric aciduria, a rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001637876).
• BP6: Variant 2-241735267-C-G is Benign according to our data. Variant chr2-241735267-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 158420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
D2HGDH	NM_152783.5	c.43C>G	p.Arg15Gly	missense_variant	2/10	ENST00000321264.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
D2HGDH	ENST00000321264.9	c.43C>G	p.Arg15Gly	missense_variant	2/10	1	NM_152783.5	P1
	ENST00000400768.2	n.232G>C		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.00840 AC: 1278 AN: 152148 Hom.: 49 Cov.: 34

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0507

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00952

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0294 AC: 3407 AN: 115976 Hom.: 212 AF XY: 0.0229 AC XY: 1479 AN XY: 64492

Gnomad AFR exome AF: 0.00378

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0480

Gnomad SAS exome AF: 0.00169

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.00582 AC: 7957 AN: 1366538 Hom.: 352 Cov.: 29 AF XY: 0.00539 AC XY: 3636 AN XY: 674148

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.0000417

Gnomad4 EAS exome AF: 0.0680

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.000896

Gnomad4 OTH exome AF: 0.00699

GnomAD4 genome AF: 0.00839 AC: 1278 AN: 152260 Hom.: 51 Cov.: 34 AF XY: 0.00936 AC XY: 697 AN XY: 74442

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.0458

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0509

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00952

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.0134

ExAC AF: 0.0105 AC: 1001

Asia WGS AF: 0.0250 AC: 87 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 10, 2016	- -

D-2-hydroxyglutaric aciduria 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	14
Dann	Benign	0.91
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.28
Sift	Benign	0.049	D
Sift4G	Uncertain	0.014	D
Polyphen		0.0	B
Vest4		0.14
MPC		0.51
ClinPred		0.0045	T
GERP RS		0.25
Varity_R		0.10
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4675887; hg19: chr2-242674682;